Many environmental agents are known to affect neural and endocrine cells such that they are stimulated to secrete a variety of biologically active products. These products, themselves, may influence many diverse physiological func-tions. In order to understand how environmental stimuli affect reproduction, we have been studying the signal transduction pathways that control luteinizing hormone-releasing hormone (LHRH), the major neurohormone regulating reproduction in mammals. Using a LHRH neuronal cell line, we have shown that alpha1-adrenergic agonists stimulate LHRH secretion from these cells. Northern blot and ligand binding analyses demonstrate that these neurons contain alpha1a/d and alpha1b receptors. These receptors are coupled to inositol phosphate production and the liberation of arachidonic acid. Some of this latter lipid is metabolized to prostaglandin E2 (PGE2) by prostaglandin H synthase (PGHS) I and II. The PGE2 is secreted into the medium of these cells where it can act in a paracrine fashion to stimulate LHRH secretion. However, the alpha1-adrenoreceptor effect on LHRH secretion is not solely attributable to PGE2 because PGHS blockage with indomethacin reduces LHRH release by only approximately 30%. The PGE2 in medium binds to prostaglandi EP1 and EP3 receptors. While the EP1 receptor appears to be coupled to inositol phosphate production and protein kinase C stimulation, several splicing variants of the EP3 receptor in the LHRH neurons render it able to couple to both phospholi- pase C and adenylyl cyclase. This former signaling pathway appears to be capable of repressing LHRH gene expression, reducing pro-LHRH biosynthesis, altering prohormone processing and stimulating secretion. Interestingly, certain cytokines such as interferon 1Beta can also stimulate PGE2 secretion in the LHRH neurons. The PGE2 pathway may be an important bridge of communication between the immune, endocrine and neuronal systems and it may represent a means whereby certain environmental agents which directly affect one of these systems may be able to affect the functions of other physiological systems.
